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Meta-Analysis
. 2024 Aug 8;14(1):18413.
doi: 10.1038/s41598-024-69064-5.

Meta-analysis of genome-wide association studies for cancer therapy-related cardiovascular dysfunction and functional mapping highlight an intergenic region close to TP63

L Martínez-Campelo  1 , A Blanco-Verea  2 , T López-Fernández  3 , A Martínez-Monzonís  4 , A Buño  5 , P Mazón  4 , P Zamora  6 , N Norton  7 , J S Reddy  8 , A Velasco-Ruiz  9 , A González-Neira  9 , C Vulsteke  10   11 , T Alonso-Gordoa  12 , R Cruz  13 , S Diz-de Almeida  13 , A Carracedo  13   14 , J R González-Juanatey  4 , J López-Sendón  15 , M Brion  2   4 ; CardioTox registry investigators
Collaborators, Affiliations
Meta-Analysis

Meta-analysis of genome-wide association studies for cancer therapy-related cardiovascular dysfunction and functional mapping highlight an intergenic region close to TP63

L Martínez-Campelo et al. Sci Rep. .

Abstract

Cancer therapy-related cardiac dysfunction (CTRCD), which commonly includes left ventricular dysfunction and heart failure, is the main adverse effect of anticancer therapy. In recent years several candidate genes studies and genome-wide association studies have identified common genetic variants associated with CTRCD, but evidence remains limited and few genetic variants are robust. A genome-wide meta-analysis of CTRCD was performed with 852 oncology patients receiving cancer therapy. DNA samples were genotyped and imputed to perform a GWAS meta-analysis for case-control (N = 852 (380 cases and 472 controls) and extreme phenotypes (N = 618 (78 cases and 472 controls) looking for genetic variants that predispose to CTRCD. The results were validated in a replicate cohort of 1,191 oncology patients (245 cases and 946 controls). Functional mapping of the replicated loci was then performed. The meta-analysis showed 9 and 17 loci suggestively associated (P-value < 1 × 10-5) with CTRCD in case-control and extreme phenotypes analyses, respectively. The 3q28 locus (rs rs7652759, P = 5.64 × 10-6) in the case-control analysis was the strongest signal, with up to 64 SNPs above the suggestive significance threshold. The rs7652759, an intergenic variant between TPRG1 and TP63 genes, was the only variant validated in the replication cohort (P-value = 0.01). Functional mapping of this significant locus revealed up to 5 new genes potentially involved in the CTRCD. We identified the intergenic region near TP63 as a novel CTRCD susceptibility locus. In the future, the genotyping of these markers could be considered in new CTRCD risk scores to improve preventive strategies in cardio-oncology.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Miami plot showing the P-values for GWAS-meta-analysis for case–control analysis (top) and extreme phenotypes (bottom). Only variants shared between the three cohorts are represented. The orange horizontal line indicates suggestive significance for common variants at − log10(1 × 10−5).Replication of the significant SNPs of the meta-analysis.
Figure 2
Figure 2
Regional plot and chromatin interactions of the locus 3q28 of the CTRCD meta-analysis. (A) Zoom in on the regional plot of the TP63 locus, which includes prioritized genes TP63, LEPREL1, KNG1, MASP1 and CLDN1. Genes prioritized by FUMA are highlighted in red. (B) Circo plot showing genes on chromosome 3 that were implicated through the genomic risk loci (blue area) by chromatin interaction mapping (orange font). The outer layer shows a Manhattan plot containing the –log10-transformed P value of each SNP in the meta-analysis. Empty regions in the Manhattan plot layer indicate regions where no SNPs with P < 0.05 were situated.
Figure 3
Figure 3
Analysis pipeline. Shows the main steps followed during the research process.
See this image and copyright information in PMC

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